UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis
UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis
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UDP-葡萄糖加速 SNAI1 mRNA 衰减并损害肺癌转移
DOI：
10.1038/s41586-019-1340-y
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发表时间：
2019-07-04
期刊：
影响因子：
64.8
通讯作者：
Yang, Weiwei
中科院分区：
文献类型：
--
作者：
Wang, Xiongjun;Liu, Ruilong;Yang, Weiwei
癌症转移是发病率和死亡率的主要原因，占癌症相关死亡的95% 1。癌细胞经常重新编程其代谢以有效地支持细胞增殖和存活2，3。然而，这些代谢改变是否以及如何有助于肿瘤细胞的迁移仍然在很大程度上未知。UDP-葡萄糖6-脱氢酶（UGDH）是糖醛酸途径中的关键酶，将UDP-葡萄糖转化为UDP-葡萄糖醛酸4。在这里，我们表明，EGFR激活后，UGDH在人肺癌细胞中的酪氨酸473磷酸化。磷酸化UGDH与Hu抗原R（HuR）相互作用并将UDP-葡萄糖转化为UDP-葡萄糖醛酸，其减弱UDP-葡萄糖介导的HuR与SNAI1 mRNA结合的抑制，因此增强SNAI1 mRNA的稳定性。SNAIL的产生增加启动上皮-间充质转化，从而促进肿瘤细胞的迁移和肺癌转移。此外，UGDH酪氨酸473磷酸化与肺癌患者的转移复发和不良预后相关。我们的研究结果揭示了UDP-葡萄糖在肺癌转移中的肿瘤抑制作用，并揭示了UGDH通过增加SNAI1 mRNA的稳定性促进肿瘤转移的机制。UDP-葡萄糖通过抑制HuR和SNAI1 mRNA之间的关联而具有肿瘤抑制作用，而UGDH介导的UDP-葡萄糖代谢导致SNAI1 mRNA稳定性和表达增加，从而促进肿瘤细胞迁移和肺癌转移。
Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial–mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA. UDP-glucose has a tumour-suppressive role by inhibiting the association between HuR and SNAI1 mRNA, whereas UGDH-mediated metabolism of UDP-glucose leads to increased SNAI1 mRNA stability and expression, thereby promoting tumour cell migration and lung cancer metastasis.